The object of the present invention is a pharmaceutical composition with a synthetic natural progesterone and oestradiol base coming in the form of a tablet, as well as a method for its preparation.
In the context of the present invention, xe2x80x9csynthetic natural progesteronexe2x80x9d is understood to mean a synthesized progesterone the chemical formula of which corresponds to the xe2x80x9cnaturalxe2x80x9d progesterone, such as is found in the female body. On the other hand, xe2x80x9csynthetic progestagensxe2x80x9d are entirely synthetic molecules such as trimegestone, norethisterone and others, the structure of which does not correspond to that of the natural progesterone.
Menopause in women can cause, indeed aggravate, certain pathologies such as oesteoporosis or cardiovascular illnesses.
Oestrogens, particularly oestradiol, are then prescribed in order to reduce these harmful consequences of menopause. But the administering of oestrogens can itself cause other undesirable effects.
It is therefore usual to combine it with a progesterone treatment in order to avoid risks of endometrical hyperplasia in particular.
It is obviously advantageous to be able to offer women these two active principles combined in the same drug in order to enable absorption in a single dose.
Drugs with a progesterone and oestradiol base in the form of tablets are already on the market. However, all the tablets known to date use synthetic progestagens, which do not have all the therapeutic effects of synthetic natural progesterone and may even have undesirable effects. The use of synthetic natural progesterone enables the effects, in particular hepatotoxic effects, of synthetic progestagens to be avoided.
With regard to natural progesterone, the Applicant Company has already perfected a drug, which is very successful at the therapeutic level. This drug comes in the form of a capsule containing micronized synthetic natural progesterone in an oil suspension. This drug is sold under the brand name UTROGESTAN.
In view of the very good results which this drug gives when it is combined with a conventional oestradiol tablet in the treatment of inconveniences associated with menopause, it would be very attractive to have a tablet with a natural progesterone and oestradiol base having a bioequivalence relative to the UTROGESTAN capsules administered in combination with an oestradiol tablet.
However it so happens that developing such a tablet causes a certain number of problems.
These problems are essentially due to the fact that, in order to be effective, natural progesterone must be used in much stronger dosages than the synthetic progestagens, i.e. 50 or 60 times more of the active principle relative to the tablet containing synthetic progestagens. The consequence is that the ratio between natural progesterone and oestradiol is about 100/1, causing problems of homogeneity in the mixture of the active principles, in the tablets as well as during their manufacture.
Another consequence lies in the percentage of excipients that can be included in the tablets. Indeed, because of the significant quantity of natural progesterone, it is necessary to considerably decrease the excipient content in view of the constraints in size and weight appropriate to tablets intended to be administered orally and/or vaginally.
It is known that excipients in the tablets play various roles. They serve to increase the stability of the active principles, to obtain a particular release profile according to their nature, but they are used above all to facilitate the compression of the different ingredients in order to obtain a tablet having good characteristics of hardness, disintegration and dissolution.
Following much work and research, the Applicant Company has succeeded in developing a new tablet with a natural progesterone and oestradiol base, meeting the homogeneity requirements of the mixture and containing only small quantities of excipients, thus making it possible to obtain tablets of a size and weight entirely acceptable for oral and/or vaginal administration.
Moreover, the Applicant Company has found that when these tablets have a particular disintegration profile, they also have a bioequivalence to the UTROGESTAN capsules combined with an oestradiol tablet, which has been demonstrated by a pharmacokinetic study comparing the two treatments. This profile is characterised by a disintegration time of less than 15 minutes, preferably less than 10 minutes, and more preferably still less than 5 minutes.
The disintegration time of the tablets is measured in a xe2x80x9cDxe2x80x9d test. According to this xe2x80x9cDxe2x80x9d test, a tablet according to the invention is placed in a one litre beaker containing 700 ml of distilled water brought to a temperature of 37xc2x0 C., and subjected to an alternating vertical motion. The time necessary for a total loss of cohesion is measured.
The invention therefore concerns a pharmaceutical composition with a natural progesterone and oestradiol base in tablet form, characterised by the fact that it has a disintegration time of less than 15 minutes, preferably less than 10 minutes, and more preferably still less than 5 minutes.
The weight ratio between the oestradiol and the progesterone is between 5/100 and 1/100, this ratio being expressed as a function of the total weight of the progesterone in the tablet.
The homogeneity of the mixture and the oestradiol/progesterone ratio were obtained by means of a wet granulation process. The oestradiol is incorporated in a binding solution before being subjected to a wetting-granulation stage, thus guaranteeing a good homogeneity of the mixture as well as a good dosage of this steroid.
Although the tablets developed by the Applicant Company contain significantly lower quantities of excipients than tablets of the prior art, they nevertheless have excellent characteristics of stability, hardness, disintegration and dissolution.
According to a preferential method of producing the invention, the pharmaceutical composition in tablet form according to the invention is characterised by the fact that the content of excipients is at most 20%, preferably at most 17%, and more preferably still at most 15%, the percentages being expressed by weight relative to the total dry matter of the tablet.
As examples of excipients that can be used in the pharmaceutical composition according to the invention, diluents, disintegrating agents, lubricants, binding agents and stripping agents may be mentioned.
Examples of diluents are starches, polyols and celluloses. Preferably, the tablet according to the invention contains in particular sodium carboxymethylcellulose.
As examples of disintegrating agents, carboxymethyl-celluloses, alginic acid as well as its sodium salt, and starches may be mentioned. Preferably, the tablet according to the invention contains reticulated sodium carboxymethyl-cellulose not only as thinner but also thanks to its disintegrating agent qualities, as well as for its strong absorbent power.
The preferred lubricant in the context of this invention is magnesium stearate.
Of the preferred binding agents in the context of this invention, one may mention polyvinylpyrollidones, but also sodium carboxymethylcellulose. This product not only enables a stable oestradiol suspension to be obtained, but also a quasi-immediate release of the active principle. Moreover it is very easy to use.
The preferred stripping agents in the context of this invention are methylhydroxypropylcellulose and polyethyleneglycol 600. It is in fact necessary to carry out the stripping in order to avoid a pure contamination.
An advantage of the tablet according to this invention is that it has a dissolution profile such that the released progesterone content is at least 75% and that the released oestradiol content is at least 75% in 15 minutes, preferably in 10 minutes, and more preferably still in 5 minutes.
The tablet according to the invention has a hardness between 10 and 80 N, preferably between 20 and 70 N, and more preferentially still between 30 and 60 N.
The invention also concerns a process for the preparation of a pharmaceutical composition with a progesterone and oestradiol base in the form of a tablet. This process is characterised by the fact that:
a wetting suspension is prepared which is mixed with an oestradiol suspension,
a first mixture of progesterone and diluent is prepared,
a second mixture of the first mixture and the wetted oestradiol suspension is prepared,
a second wetting of the product of this second mixture is carried out,
a granulation of the product of the wetting is carried out, in order to obtain a granular product,
disintegrating agents and diluents are added to the granular product in order to obtain a third mixture,
a lubricant is added to the third mixture in order to obtain a fourth mixture,
a compression of the fourth mixture is carried out in order to obtain tablets,
stripping of the tablets is carried out.
According to a preferential method of producing the invention, the granulation is followed by unclotting, drying, then grading.